Combinations comprising 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline

ABSTRACT

The combination of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a pharmaceutically acceptable salt thereof with a second therapeutic agent, and its use for the treatment of a) psychiatric disorders with prominent cognitive deficits e.g. chronic PTSD (Post traumatic stress disorder); b) non-degenerative disorders with prominent cognitive deficits e.g. MS (multiple Sclerosis), post-chemotherapy, post-CABG (Coronary artery bypass graft), post-stroke; and/or c) paediatric disorders e.g. autism, mental retardation and learning disabilities, in particular for the treatment of schizophrenia.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 14/802,036, filed on Jul. 17, 2015, which is acontinuation application of U.S. patent application Ser. No. 12/746,968filed on Jun. 9, 2010, which is a National Stage filing under 35 U.S.C.§ 371 of International Patent Application No. PCT/EP2008/067225, filedDec. 10, 2008, which claims the priority of United Kingdom ApplicationNos. 0724281.1 and 0724285.2, both filed on Dec. 12, 2007, the contentswhich are incorporated herein by reference in their entireties.

The present application relates to new uses of 5-HT₆ receptorantagonists, specifically 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline,and to the combination of 5-HT₆ receptor antagonists, specifically3-phenylsulfonyl-8-piperazinyl-1yl-quinoline, with a second therapeuticagent.

WO03/080580 discloses compounds of formula (I) and pharmaceuticallyacceptable salts thereof:

wherein:

R¹ and R² independently represent hydrogen or C₁₋₆ alkyl or R¹ is linkedto R² to form a group (CH₂)₂, (CH₂)₃ or (CH₂)₄;

R³, R⁴ and R⁵ independently represent hydrogen, halogen, cyano, —CF₃,—CF₃O, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆ alkanoyl or a group —CONR⁶R⁷;

R⁶ and R⁷ independently represent hydrogen or C₁₋₆ alkyl or together maybe fused to form a 5- to 7-membered aromatic or non-aromaticheterocyclic ring optionally interrupted by an O or S atom;

m represents an integer from 1 to 4, such that when m is an integergreater than 1, two R² groups may instead be linked to form a group CH₂,(CH₂)₂ or (CH₂)₃;

n represents an integer from 1 to 3;

p represents 1 or 2;

A represents a group —Ar¹ or —Ar²Ar³;

Ar¹, Ar² and Ar³ independently represent an aryl group or a heteroarylgroup, both of which may be optionally substituted by one or more (eg.1, 2 or 3) substituents which may be the same or different, and whichare selected from the group consisting of halogen, hydroxy, cyano,nitro, trifluoromethyl, trifluoromethoxy, C₁₋₆ alkyl,trifluoromethanesulfonyloxy, pentafluoroethyl, C₁₋₆ alkoxy, arylC₁₋₆alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkoxyC₁₋₆ alkyl, C₃₋₇ cycloalkylC₁₋₆alkoxy, C₁₋₆ alkanoyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆ alkyl sulfonyloxy, C₁₋₆ alkyl sulfonylC₁₋₆ alkyl,aryl sulfonyl, aryl sulfonyloxy, aryl sulfonylC₁₋₆ alkyl, C₁₋₆alkylsulfonamido, C₁₋₆ alkylamido, C₁₋₆ alkylsulfonamidoC₁₋₅ alkyl, C₁₋₆alkylamidoC₁₋₆ alkyl, arylsulfonamido, arylcarboxamido,arylsulfonamidoC₁₋₆ alkyl, arylcarboxamidoC₁₋₆ alkyl, aroyl, aroylC₁₋₆alkyl, arylC₁₋₆ alkanoyl, or a group CONR⁸R⁹ or SO₂NR⁸R⁹, wherein R⁸ andR⁹ independently represent hydrogen or C₁₋₆ alkyl or together may befused to form a 5- to 7-membered aromatic or non-aromatic heterocyclicring optionally interrupted by an C or S atom;

or solvates thereof.

Specifically disclosed is 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline(Example 16) and its hydrochloride salt (Example 2).

3-Phenylsulfonyl-8-piperazinyl-1yl-quinoline can be prepared asdescribed in WO03/080580 or by the further process described inWO07/039238. WO05/040124 discloses a further polymorphic form of3-phenylsulfonyl-8-piperazinyl-1yl-quinoline as Form III. TheseInternational Patent Applications are incorporated herein in theirentirety.

Compounds of formula (I) and their pharmaceutically acceptable salts aredisclosed in WO03/080580 as having affinity for the 5-HT₆ receptor andare believed to be of potential use in the treatment of certain CNSdisorders such as anxiety, depression, epilepsy, obsessive compulsivedisorders, migraine, cognitive memory disorders (e.g. Alzheimersdisease, age related cognitive decline and mild cognitive impairment),Parkinsons Disease, ADHD (Attention Deficit Disorder/HyperactivitySyndrome), sleep disorders (including disturbances of Circadian rhythm),feeding disorders such as anorexia and bulimia, panic attacks,withdrawal from drug abuse such as cocaine, ethanol, nicotine andbenzodiazepines, schizophrenia (in particular cognitive deficits ofschizophrenia), stroke and also disorders associated with spinal traumaand/or head injury such as hydrocephalus. WO03/080580 also disclosesthat Compounds of formula (I) and their pharmaceutically acceptablesalts are expected to be of use in the treatment of certain GI(gastrointestinal) disorders such as IBS (Irritable Bowel Syndrome) andin the treatment of obesity.

It will be appreciated by those skilled in the art that the termcognitive memory disorders includes other neurodegenerative disordersassociated with dementia, e.g. VaD (Vascular Dementia), DLB (dementiawith Lewy Bodies), Mixed AD+CVD (Alzheimer's Disease and CardiovascularDisease) and HD (Huntingdon's Disease).

US2007/0167431 and WO07/087151 (both Wyeth) disclose a method for thetreatment of a cognitive disorder such as Alzheimer's disease in apatient in need thereof which comprises providing to said patient atherapeutically effective amount of a combination of anacetylcholinesterase inhibitor and a 5-HT₆ receptor antagonist.

US2007/0167431 discloses that the acetylcholinesterase inhibitorssuitable for use are donepezil (i.e. Aricept™ manufactured by Pfizer),galanthamine (i.e. Razadyne™, manufactured by Johnson and Johnson),rivastigmine (i.e. Exelon™, manufactured by Novartis) or any othercompounds known to inhibit acetylcholinesterase. A number of patentapplications were cited therein which disclosed 5-HT6 antagonistssuitable for use. Furthermore the following 5HT6 compounds were listedby name, 3-(1-naphthylsulfonyl)-5-piperazin-1yl-1H-indazole,N,N-dimethyl-3-{3-(1-naphthylsulphonyl)-1H-indazol-5-yl]oxy}propan-1-amine,(2-{[3-(1-naphthylsulphonyl)-1H-indazol-7-yl]oxy}ethyl)amine, 1-(phenylsulphonyl)-4-(1-piperazinyl)-1H-indazole,5-chloro-N-[4-methoxy-3-(1-piperazinyl)phenyl]-3-methylbenzo(b)thiophene-2-sulfonamide(SB-271046),4-amino-N-[2,6-bis(methylamino)pyrimidin-4-yl]benzenesulfonamide (Ro04-6790, 4-amino-N-[2,6-bis(methylamino)pyridin-4-y]benzenesulfonamide(Ro 63-0563), SB357134, SB399885, GSK-742457, LY4833518/SGS-518,Ro43-68554 and PRX-07034.

The present invention provides the combination of a 5-HT₆ receptorantagonist, specifically 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline ora pharmaceutically acceptable salt thereof, with a second therapeuticagent. In one embodiment the present invention provides a combination of3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a pharmaceuticallyacceptable salt thereof with a therapeutic agent known to modifycholinergic transmission such as M1 muscarinic receptor agonists orallosteric modulators, M2 muscarinic antagonists, acetylcholinesteraseinhibitors, nicotinic receptor agonists or allosteric modulators, 5-HT4receptor partial agonists or 5HT1A receptor antagonists and NMDAreceptor antagonists or modulators, glutamate antagonists, GABA-ergicantagonists, H3 antagonists, putative metabolic/mitochondrialmodulators, or disease modifying agents such as β or γ-secretaseinhibitors, Tau-targeted therapeutics, β-amyloid aggregation inhibitorsand β-amyloid immunotherapies.

Examples of putative metabolic/mitochondrial modulators are Ketasyn™,RSG-XR, intranasal insulin and Dimebon.

Examples of β-amyloid aggregation inhibitors and β-amyloidimmunotherapies include PBT2 (Prana Biotechnology), ELND005/AZD-103(Elan and Transition Therapeutics), Gammagard/IGIV (BaxterInternational), monoclonal antibody LY2062430 (Eli Lilly), andbapineuzumab (Wyeth/Elan).

Examples of Tau-targeted therapeutics include tetramethylthioninechloride (REMBER™, TauRX) and AL-108 (Allon).

This combination may be useful in the treatment of cognitive memorydisorders, for example Alzheimer's disease, age related cognitivedecline and mild cognitive impairment, neurodegenerative disorders forexample dementia including vascular dementia (VaD), dementia with LewyBodies (DLB), Alzheimer's Disease and Cardiovascular Disease (MixedAD+CVD) and Huntingdon's Disease (HD).

Accordingly the present invention also provides a method for thetreatment of cognitive memory disorders, for example Alzheimer'sdisease, age related cognitive decline and mild cognitive impairment,neurodegenerative disorders for example dementia including vasculardementia (VaD), dementia with Lewy Bodies (DLB), Alzheimer's Disease andCardiovascular Disease (Mixed AD+CVD) and Huntingdon's Disease (HD) in apatient in need thereof which comprises providing to said patient atherapeutically effective amount of a combination of3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a pharmaceuticallyacceptable salt thereof, with a therapeutic agent known to modifycholinergic transmission such as M1 muscarinic receptor agonists orallosteric modulators, M2 muscarinic antagonists, acetylcholinesteraseinhibitors, nicotinic receptor agonists or allosteric modulators, 5-HT4receptor partial agonists or 5HT1A receptor antagonists and NMDAreceptor antagonists or modulators, glutamate antagonists, GABA-ergicantagonists, H3 antagonists, putative metabolic/mitochondrialmodulators, or disease modifying agents such as β or γ-secretaseinhibitors, Tau-targeted therapeutics, β-amyloid aggregation inhibitorsand β-amyloid immunotherapies.

One embodiment is directed to combinations of3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a pharmaceuticallyacceptable salt thereof and a second therapeutic agent selected fromdonepezil, rivastigmine, tetrahydroaminoacridine, memantine,galantamine, 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamidehydrochloride or1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone.

At a mechanistic level, pharmacodynamic interactions between anacetylcholinesterase inhibitor and a 5HT₆ receptor antagonist arefeasible. In preclinical studies in rats3-phenylsulfonyl-8-piperazinyl-1yl-quinoline induces a small increase inthe extra cellular levels of acetylcholine in the prefrontal cortex.Although the underlying mechanism is still unknown, it is likely due toincreases in the release of acetylcholine from cholinergic neurons, Onthe other hand, donepezil increases the extracellular levels ofacetylcholine by inhibiting the acetylcholinesterase to reduce thedegradation of acetylcholine. Therefore this action may prevent thedegradation of acetylcholine induced by3-phenylsulfonyl-8-piperazinyl-1yl-quinoline resulting in a netincreased level of acetylcholine that may influence cognitive functions.

In another embodiment the present invention provides a combination of3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a pharmaceuticallyacceptable salt thereof with an antidepressant, for example a tricyclic,a MAOI (Monoamine oxidase inhibitor) a SSRI (Selective SerotoninReuptake Inhibitor), a SNRI (Serotonin and Noradrenaline ReuptakeInhibitor) or a NaSSA (noradrenergeric and specific serotonergicantidepressant). Examples of specific antidepressant compounds aredescribed below.

Medication Trade name Group Amitriptyline Tryptizol TricyclicClomipramine Anafranil Tricyclic Citalopram Cipramil SSRI DosulepinProthiaden Tricyclic Doxepin Sinequan Tricyclic Fluoxetine Prozac SSRIImipramine Tofranil Tricyclic Lofepramine Gamanil Tricyclic MirtazapineZispin NaSSA Moclobemide Manerix MAOI Nortriptyline Allegron TricyclicParoxetine Seroxat SSRI Phenelzine NardiI MAOI Reboxetine Edronax SNRISertraline Lustral SSRI Tranylcypromine Parnate MAOI Trazodone MolipaxinTricyclic-related Venlafaxine Efexor SNRI

In a further embodiment the present invention provides a combination of3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a pharmaceuticallyacceptable salt thereof and an atypical antipsychotic, for exampleolanzapine, clozapine, prisperidone, quentiapine, aripriprazole orpaliperiden.

This combination may be useful in the treatment of schizophrenia.Accordingly, in yet another aspect the present invention provides amethod for the treatment of schizophrenia in a patient in need thereofwhich comprises providing to said patient a therapeutically effectiveamount of a combination of 3-phenylsulfonyl-8-piperazinyl-1yl-quinolineor a pharmaceutically acceptable salt thereof, with an atypicalantipsychotic, for example olanzapine, clozapine, prisperidone,quentiapine, aripriprazole or paliperiden.

In a further embodiment the present invention provides a combination of3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a pharmaceuticallyacceptable salt thereof and a second therapeutic agent suitable for usein Attention Deficit Disorders/Hyperactivity Syndrome, e.g.methylphenidate (Ritalin) or dexamfetamine (Dexedrine).

In a further aspect the present invention also provides the use of acombination of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or apharmaceutically acceptable salt thereof and a second therapeutic agentin the manufacture of a medicament for use in the treatment of the abovedisorders.

Accordingly, in one embodiment the present invention provides the use ofa combination of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or apharmaceutically acceptable salt thereof with a therapeutic agent knownto modify cholinergic transmission such as M1 muscarinic receptoragonists or allosteric modulators, M2 muscarinic antagonists,acetylcholinesterase inhibitors, nicotinic receptor agonists orallosteric modulators, 5-HT4 receptor partial agonists or 5HT1A receptorantagonists and NMDA receptor antagonists or modulators, glutamateantagonists, GABA-ergic antagonists, H3 antagonists, putativemetabolic/mitochondrial modulators, or disease modifying agents such asβ or γ-secretase inhibitors, Tau-targeted therapeutics, β-amyloidaggregation inhibitors and β-amyloid immunotherapies, in the manufactureof a medicament for use in the treatment of cognitive memory disorders,for example Alzheimer's disease, age related cognitive decline and mildcognitive impairment, neurodegenerative disorders for example dementiaincluding vascular dementia (VaD), dementia with Lewy Bodies (DLB),Alzheimer's Disease and Cardiovascular Disease (Mixed AD+CVD) andHuntingdon's Disease (HD).

In another embodiment the present invention provides the use of acombination of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or apharmaceutically acceptable salt thereof and an atypical antipsychotic,for example olanzapine, clozapine, prisperidone, quentiapine,aripriprazole or paliperiden in the manufacture of a medicament for usein the treatment of schizophrenia.

The present invention is also directed to new uses of3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a pharmaceuticallyacceptable salt thereof; specifically

-   -   a) further psychiatric disorders with prominent cognitive        deficits e.g. chronic PTSD (Post traumatic stress disorder);    -   b) non-degenerative disorders with prominent cognitive deficits:        MS (multiple Sclerosis), post-chemotherapy, post-CABG (Coronary        artery bypass graft), post-stroke; and    -   c) paediatric disorders: autism, mental retardation and learning        disabilities.

The invention further provides a method of treatment or prophylaxis ofthese disorders, in mammals including humans, which comprisesadministering to the sufferer a therapeutically effective amount of3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a pharmaceuticallyacceptable salt thereof.

The invention also provides the use of a3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a pharmaceuticallyacceptable salt thereof in the manufacture of a medicament for use inthe treatment or prophylaxis of these disorders.

The invention also provides combinations of3-phenylsulfonyl-8-piperazinyl-1yl-quinoline and a second therapeuticagent for use in these disorders.

In respect of the treatment of PTSD, the second therapeutic agent may beselected from: serotonergic antidepressants (SSRIs), e.g. fluoxetine(Prozac), sertraline (Zoloft), paroxetine (Paxil), trazodone (Desyrel);medicines that help decrease the physical symptoms associated with PTSD,e.g. clonidine (Catapres), guaneficine (Tenex), and propranolol; moodstabilizers such as lamotrigine (Lamictal), tiagabine (Gabitril),divalproex sodium (Depakote); monoamine oxadazine inhibitors, phenelzine(Nardil); antiadrenergic agents, e.g. clonidine (Catapres), propanolol(lnderal) and guanfacine (Tenex), mood stabilizers that are alsoantipsychotics, like risperidone (Risperdal), olanzapine (Zyprexa), andquetiapine (Seroquel).

In respect of the treatment of MS, the second therapeutic agent may beselected from: steroids, e.g. methylprednisolone (eg Depo-Medrone),prednisone, dexamethasone disease-modifying agents e.g. interferonbeta-la (Avonex or Rebif), interferon beta-1b (Betaferon), glatirameracetate (Copaxone) injections or mitoxantrone (Novantrone); symptomaticagents e.g. Muscle Relaxants (Baclofen, Dantrolene, Tizanidine,Cyclobenzaprine, Clonazepam, Diazepam); Anticholinergics (Propantheline,Tolterodine Dicyclomine); Urinary Tract Antispasmodics (Oxybutynin);Tricyclic Antidepressants (Amitriptyline, Imipramine); AntidiureticHormone (desmopressin and desmopressin acetate); Anticonvulsants(carbamazepine, phenytoin, acetazolamide, lamotrigine); Central NervousSystem Stimulants (pemoline); Selective Serotonin Reuptake Inhibitors(SSRIs) (citalopram, fluoxetine, paroxetine, sertraline); Non-SteroidalAnti-Inflammatory Drugs (NSAIDS) (ibuprofen, naproxen, ketoprofen); andPhosphodiesterase-5 Inhibitors (sildenafil, tadalafil, vardenafil).

Additionally the second therapeutic agent for use in the treatment of MSor its associated symptoms may be selected from an H3 receptorantagonist,6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamidehydrochloride or1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone;S1P1 agonists; anti-CD20 monoclonal antibody therapies such asrituximab, ofatumumab; anti-CD3 monoclonal antibody therapies such asotelixizumab; rosiglitazone (Avandia™), alpha 4 integrin antagonist e.gfirategrast, natalizumab (TYSABRI™).

Additionally the second therapeutic agent for use in the treatment of MSor its associated symptoms may be selected from BG12 (Biogen Idec), anS1P agonist e.g. Fingolimod, an immunosuppressant e.g. Laquinimod,Teriflunomide; an estrogen agonist e.g. Trimesta.

In respect of the treatment post chemotherapy, the second therapeuticagent may be selected from: Aldesleukin or IL-2 (Proleukin), Alemtuzumab(MabCampath), Amsacrine (acridinyl anisidide; m-AMSA), Anastrozole(Arimidex), Asparaginase (Crisantaspase), Bevacizumab (Avastin),Bicalutamide (Casodex), Bleomycin, Bortezomib (Velcade), Busulfan,(Campto) Irinotecan, Capecitabine (Xeloda) Carboplatin (Paraplatin),Carmustine (BCNU), Cetuximab, Chlorambucil, Cisplatin, Cladribine(2-CdA, Leustatin), Co-codamol, Cyclophosphamide, Cyproterone acetate(Cyprostat), Cytarabine (Ara C, cytosine arabinoside), Dacarbazine(DTIC), Dactinomycin (Actinomycin D), Daunorubicin, Disodium pamidronate(Aredia), Docetaxel (Taxotere), Doxorubicin, Epirubicin, Erlotinib(Tarceva), Estramustine (Emcyt, Estracyte), Etoposide (VP16, Etopophos),Exemestane (Aromasin), Fentanyl (Durogesic), Fludarabine, Fluorouracil(5FU), Flutamide (Drogenil), Gemcitabine (Gemzar), (Herceptin)Trastuzumab, Goserelin (Zoladex) for breast cancer, Goserelin (Zoladex)for prostate cancer, Hydroxycarbamide (used to be called hydroxyurea),Ibandronic acid (Bondronat), Ibritumomab (Zevalin), Ibuprofen,Idarubicin (Zavedos) Ifosfamide, Imatinib (Glivec), Interferon (Roferon,Intron A), Irinotecan (Campto), Interleukin, lapatinib (Tykerb),Letrozole (Femara), Liposomal Doxorubicin (Caelyx, Myocet, Doxcil),Lomustine (CCNU), Melphalan, Mercaptopurine (6-MP, Purinethol),Methotrexate, Mitomycin C, Mitoxantrone, Morphine, Oxaliplatin,Paclitaxel (Taxol), Pentostatin, Procarbazine, Raltitrexed (Tomudex),Rituximab (Mabthera), Sodium clodronate (Bonefos, Loron), Streptozocin(Zanosar), Steroids, Tamoxifen, (Taxol) Paclitaxel, (Taxotere)Docetaxel, Tegafur with uracil (Uftoral), Temozolomide (Temodal),Tioguanine (Lanvis, 6-TG, 6-tioguanine, Tabloid), Thiotepa (Thioplex,Triethylenethiophosphoramide), (Tomudex) Raltitrexed, Topotecan(Hycamtin), Tretinoin (Vesanoid, ATRA), Treosulfan, Vinblastine(Velban), Vincristine (Oncovin) Vindesine (Eldisine), Vinorelbine(Navelbine), Zevalin (90Y Ibritumomab tiuxetan) and Zoledronic acid(Zometa).

Specifically the second therapeutic agent may be lapatinib, which mayalso be used in conjunction with capecitabine.

In respect of treatment after a stroke, the second therapeutic agent maybe selected from alteplase (Actilyse), aspirin, dipyridamole,fluvastatin sodium (Lescol), clopidogrel hydrogen sulphate (Plavix),ramipril (Tritace) and simvastatin (Simvador, Zocor).

It will be appreciated that reference to treatment is intended toinclude prophylaxis as well as the alleviation of established symptoms.

The two therapeutic agents may be administered simultaneously orsequentially and, when administration is sequential, either may beadministered first. When administration is simultaneous, the combinationmay be administered either in the same or different pharmaceuticalcomposition.

The two therapeutic agents may be used either as separate formulationsor as a single combined formulation. When combined in the sameformulation it will be appreciated that the two compounds must be stableand compatible with each other and the other components of theformulation.

Therefore, in further aspect the present invention also providespharmaceutical compositions comprising an effective amount of acombination of a 5-HT₆ receptor antagonist, specifically3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a pharmaceuticallyacceptable salt thereof and a second therapeutic agent, and apharmaceutically acceptable carrier.

In one embodiment the second therapeutic agent is an agent known tomodify cholinergic transmission such as M1 muscarinic receptor agonistsor allosteric modulators, M2 muscarinic antagonists,acetylcholinesterase inhibitors, nicotinic receptor agonists orallosteric modulators, 5-HT4 receptor partial agonists or 5HT1A receptorantagonists and NMDA receptor antagonists or modulators, glutamateantagonists GABA-ergic antagonists, H3 antagonists or disease modifyingagents such as β or γ-secretase inhibitors.

In another embodiment the second therapeutic agent is an antidepressant,for example a tricyclic, a MAOI (Monoamine oxidase inhibitor) a SSRI(Selective Serotonin Reuptake Inhibitor), a SNRI (Serotonin andNoradrenaline Reuptake Inhibitor) or a NaSSA (noradrenergeric andspecific serotonergic antidepressant).

In another embodiment the second therapeutic agent is an atypicalantipsychotic, for example olanzapine, clozapine, prisperidone,quentiapine, aripriprazole or paliperiden.

In another embodiment the second therapeutic agent is a therapeuticagent suitable for use in Attention Deficit Disorders/HyperactivitySyndrome, e.g. methylphenidate (Ritalin) or dexamfetamine (Dexedrine).

When formulated separately they may be provided in any convenientformulation, conveniently in such manner as are known for such compoundsin the art.

A pharmaceutical composition may be prepared by admixture, suitably atambient temperature and atmospheric pressure, and is usually adapted fororal, parenteral or rectal administration and, as such, may be in theform of tablets, capsules, oral liquid preparations, powders, granules,lozenges, reconstitutable powders, injectable or infusable solutions orsuspensions or suppositories. Orally administrable compositions aregenerally preferred.

Tablets and capsules for oral administration may be in unit dose form,and may contain conventional excipients, such as binding agents,fillers, tabletting lubricants, disintegrants and acceptable wettingagents. The tablets may be coated according to methods well known innormal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, emulsifying agents,non-aqueous vehicles (which may include edible oils), preservatives,and, if desired, conventional flavourings or colourants.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound and a sterile vehicle. The compound, depending onthe vehicle and concentration used, can be either suspended or dissolvedin the vehicle. In preparing solutions, the compound can be dissolvedfor injection and filter sterilised before filling into a suitable vialor ampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, preservatives and buffering agents are dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilization cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspension in a sterilevehicle. Advantageously, a surfactant or wetting agent is included inthe composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from10 to 60% by weight, of the active material, depending on the method ofadministration.

Compositions may, if desired, be presented in a pack or dispenser devicewhich may contain one or more unit dosage forms containing the activeingredients. The pack may, for example, comprise metal or plastic foil,such as a blister pack. Where the compounds are intended foradministration as two separate compositions these may be presented, forexample, in the form of a twin pack.

Pharmaceutical compositions may also be prescribed to the patient in“patient packs” containing the whole course of treatment in a singlepackage, usually a blister pack. Patient packs have an advantage overtraditional prescriptions, where a pharmacists divides a patients supplyof a pharmaceutical from a bulk supply, in that the patient always hasaccess to the package insert contained in the patient pack, normallymissing in traditional prescriptions. The inclusion of a package inserthas been shown to improve patient compliance with the physiciansinstructions.

It will be understood that the administration of the combination bymeans of a single patient pack, or patient packs of each composition,including a package insert directing the patient to the correct use ofthe combination is a desirable additional embodiment.

According to a further embodiment there is provided a patient packcomprising at least one active ingredient, of the combination and aninformation insert containing directions on the use of the combination.

According to another embodiment there is provided a double packcomprising in association for separate administration of3-phenylsulfonyl-8-piperazinyl-1yl-quinoline and the second therapeuticagent.

The dose of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline used in thetreatment of the aforementioned disorders will vary in the usual waywith the seriousness of the disorders, the weight of the sufferer, andother similar factors. However, as a general guide suitable unit dosesmay be 0.05 to 1000 mg, more suitably 0.05 to 200 mg, for example 20 to40 mg; and such unit doses will preferably be administered once a day,although administration more than once a day may be required; and suchtherapy may extend for a number of weeks or months.

The dose of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline used incombination with a second therapeutic agent may be same as when it isused on its own or may be different. It may be possible that the dose ofeither drug used may be lower when used in combination than when usedseparately.

Suitable behavioural models of cognition known to the person of ordinaryskill in the art, for example object recognition memory in youngSprague-Dawley and aged Fisher rats, Water Maze model to investigatespatial learning and memory in young and aged Fisher rats.

A suitable animal model for studying therapeutic drugs againstpost-traumatic stress disorder is described by Aharon Levy, in MilitaryMedicine, December 2001.

A suitable animal model for studing multiple sclerosis is theexperimental autoimmunal encephalomyelitis (EAE) model.

Patient Study for Schizophrenia

The study may be performed as a multicenter, double-blind, placebocontrolled randomised, parallel group determination of efficacy of3-phenylsulfonyl-8-piperazinyl-1yl-quinoline in combination with anatypical antipsychotic agent approved for the treatment of schizophreniavs an atypical antipsychotic agent approved for the treatment ofschizophrenia with placebo.

For example, the study may be performed using a therapeutic dose withinthe prescribed guidelines of Risperidone.

The patients may receive an appropriate dose of the atypicalantipsychotic agent (defined antipsychotic agent or antipsychotic) ,and,depending on which group they belonged, a therapeutically effectiveamount 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline once daily orplacebo over 12 weeks after a brief wash-out period of earlierantipsychotic medication.

During the wash-out period, a benzodiazepine preparation (mostlylorazepam) may be prescribed, if necessary. Patients with agitation,anxiety, or sleeping problems may be also medicated with lorazepamduring the study.

Efficacy and tolerability of3-phenylsulfonyl-8-piperazinyl-1yl-quinoline/antipsychotic agent vsplacebo/antipsychotic agent will be assessed using the followingendpoints—positive and negative syndrome scale (PANSS), Clinical GlobalImpression score (CGI), AIMS, Simpson and Angus, Barnes Akathisia,Calgary Depression Scale and cognition endpoints.

The use of biperiden may be monitored as a possible indicator for sideeffects of the antipsychotic medication.

In order to exclude the chance that possible differences in thetherapeutic effectiveness between the two groups might be due tonon-compliance during the antipsychotic therapy or to differences in theantipsychotic agent metabolism, the plasma levels of this drug may bemonitored during the study.

The statistics may be performed according to the criterion of “lastobservation carried forward” (LOCF), i. e., the last PANSS scores of thepatients who dropped out before the end of the study were carriedforward to all subsequent observation days.

For the comparison of the main efficacy parameter, the mean change inthe PANSS between the two treatment groups, t-tests for independentsamples may be employed. With reference to the underlying hypothesis ofa better outcome of3-phenylsulfonyl-8-piperazinyl-1yl-quinoline/antipsychotic agent group,a significance of p<0.05 may be calculated in the one-tailed t-test andused as the basis for the estimation of the sample size (statisticalpower) and for the comparison of the groups. For all other comparisons,two-tailed t-tests may be used.

The improved effectiveness of the combination therapy with3-phenylsulfonyl-8-piperazinyl-1yl-quinoline/antipsychotic agent incomparison to antipsychotic monotherapy may be clearly shown by thesignificantly lower PANSS global scores after the 2^(nd) to 12 weeks oftreatment.

Therefore, it could be excluded that the observed differences in thetherapeutic effectiveness between the two groups may be due toincompatibility during the antipsychotic agent therapy or differences inantipsychotic metabolism.

The combination of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline and anatypical antipsychotic agent according to the present invention thus mayshow improved results compared to the monopreparation of the atypicalantipsychotic agent with regard to effectiveness in the treatment ofschizophrenia.

Depression/Anxiety Study

Activity of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline in combinationwith SSRI inhibitors, vs. depression/anxiety may be evaluated accordingto the following models:

Porsolt test in mouse for SSRI/TCA (tricyclic antidepressants) (Porsoltet al 1977, Arch Int Pharmacodyn Ther,: 229, 327-336);

Chronic mild stress in rat for SSRI/TCA (Willner, 1991, TiPS,: 12,131-136);

Maternal deprivation in rat pups for SSRI (or modulator of serotoninreceptors)/TCA (Gardner, 1985, J. Pharmacol. Methods 14: 181-187);

Rat social interaction after chronic treatment with SSRI/TCA (File, 1980J. Neurosci Methods, 2:219-238; Lightowler et al., 1994, Pharmacol.,Biochem. Behaviour,: 49, 281-285);

Gerbil social interaction after chronic treatment with SSRI (ormodulator of serotonin receptors)/TCA (File, 1997, Pharmacol. Biochem.Behay. 58: 747-752).

Clinical Trials

The usefulness of the compound for treating a Depressive Disorder can besupported by the following studies as described.

Clinical Observations

A double-blind multicenter clinical trial may be designed to assess thesafety and efficacy of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline ofthe present invention in combination with an SSRI such as paroxetine fortreatment of Bipolar Disorder, Bipolar Depression or UnipolarDepression. Patients are randomized to3-phenylsulfonyl-8-piperazinyl-1yl-quinoline, an SSRI such as paroxetineor 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline plus an SSRI.

In one such study, an 8-week, double blind trial, 28 patients diagnosedwith treatment-resistant major depression would be randomized to one ofthree treatment arms: (1) paroxetine and placebo; (2)3-phenylsulfonyl-8-piperazinyl-1yl-quinoline and placebo; or (3)paroxetine plus 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline. Theefficacy of the treatment may be monitored using the HAMD-21 (HamiltonM. Journal of Neurology, Neurosurgery & Psychiatry, 1960.23: 56-62, andHamilton M. Development of a rating scale for primary depressiveillness. British Journal of Social and Clinical Psychology. 1967;6:278-296), Montgomery-Asberg Depression Rating Scale (MADRS)(MontgomeryS A, Asberg M. A new depression scale designed to be sensitive tochange. British Journal of Psychiatry. 1979;134:382-389), and theClinical Global Impression (CGI)—Severity of Depression rating scale(Guy, W. ECDEU Assessment Manual for Psychopharmacology. Revised ed. USDept of Health, Education and Welfare, Bethesda, Md. 1976).

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

1. -6. (canceled)
 7. A method of treating a cognitive memory disorder ina patient in need thereof comprising administering to said patient morethan 40 mg of 3-phenylsulfonyl-8-piperazinyl-1-yl-quinoline or apharmaceutically acceptable salt thereof, and a therapeuticallyeffective amount of an acetylcholinesterase inhibitor; wherein saidcognitive memory disorder is selected from the group consisting ofAlzheimer's disease, age related cognitive decline, mild cognitiveimpairment, dementia associated with mixed Alzheimer's disease,cardiovascular disease, vascular dementia, dementia with Lewy Bodies,and dementia associated with Huntingdon's disease.
 8. The method ofclaim 7, wherein the cognitive memory disorder is Alzheimer's disease.9. The method of claim 7, wherein the acetylcholinesterase inhibitor isselected from donepezil, galanthamine, rivastigmine, and any combinationthereof.
 10. The method of claim 7, wherein the dose of3-phenylsulfonyl-8-piperazinyl-1-yl-quinoline or a pharmaceuticallyacceptable salt thereof, is administered once a day.
 11. The method ofclaim 7, wherein the dose of3-phenylsulfonyl-8-piperazinyl-1-yl-quinoline or a pharmaceuticallyacceptable salt thereof, is administered more than once a day.
 12. Amethod for the treatment of a cognitive memory disorder in a patient inneed thereof comprising administering to said patient a pharmaceuticalcomposition comprising more than 40 mg of3-phenylsulfonyl-8-piperazinyl-1-yl-quinoline or a pharmaceuticallyacceptable salt thereof, a therapeutically effective amount of anacetylcholinesterase inhibitor, and a pharmaceutically acceptablecarrier; wherein said cognitive memory disorder is selected from thegroup consisting of Alzheimer's disease, age related cognitive decline,mild cognitive impairment, dementia associated with mixed Alzheimer'sdisease, cardiovascular disease, vascular dementia, dementia with LewyBodies, and dementia associated with Huntingdon's disease.
 13. Themethod of claim 12, wherein the cognitive memory disorder is Alzheimer'sdisease.
 14. The method of claim 12, wherein the acetylcholinesteraseinhibitor is selected from donepezil, galanthamine, rivastigmine, andany combination thereof.
 15. The method of claim 12, wherein the dose of3-phenylsulfonyl-8-piperazinyl-1-yl-quinoline or a pharmaceuticallyacceptable salt thereof, is administered once a day.
 16. The method ofclaim 12, wherein the dose of3-phenylsulfonyl-8-piperazinyl-1-yl-quinoline or a pharmaceuticallyacceptable salt thereof, is administered more than once a day.
 17. Amethod for improving the cognitive function of a patient suffering fromone or more of Alzheimer's disease, age related cognitive decline, mildcognitive impairment, dementia associated with mixed Alzheimer'sdisease, cardiovascular disease, vascular dementia, dementia with LewyBodies, and dementia associated with Huntingdon's disease, comprisingadministering to said patient more than 40 mg of3-phenylsulfonyl-8-piperazinyl-1-yl-quinoline or a pharmaceuticallyacceptable salt thereof, and a therapeutically effective amount of anacetylcholinesterase inhibitor.
 18. The method of claim 17, wherein theacetylcholinesterase inhibitor is selected from donepezil, galanthamine,rivastigmine, and any combination thereof.
 19. The method of claim 17,wherein the dose of 3-phenylsulfonyl-8-piperazinyl-1-yl-quinoline or apharmaceutically acceptable salt thereof, is administered once a day.20. The method of claim 17, wherein the dose of3-phenylsulfonyl-8-piperazinyl-1-yl-quinoline or a pharmaceuticallyacceptable salt thereof, is administered more than once a day.
 21. Amethod for improving the cognitive function of a patient suffering fromone or more of Alzheimer's disease, age related cognitive decline, mildcognitive impairment, dementia associated with mixed Alzheimer'sdisease, cardiovascular disease, vascular dementia, dementia with LewyBodies, and dementia associated with Huntingdon's disease, comprisingadministering to said patient a pharmaceutical composition comprisingmore than 40 mg of 3-phenylsulfonyl-8-piperazinyl-1-yl-quinoline or apharmaceutically acceptable salt thereof, a therapeutically effectiveamount of an acetylcholinesterase inhibitor; and a pharmaceuticallyacceptable carrier.
 22. The method of claim 21, wherein theacetylcholinesterase inhibitor is selected from donepezil, galanthamine,rivastigmine, and any combination thereof.
 23. The method of claim 21,wherein the dose of 3-phenylsulfonyl-8-piperazinyl-1-yl-quinoline or apharmaceutically acceptable salt thereof, is administered once a day.24. The method of claim 21, wherein the dose of3-phenylsulfonyl-8-piperazinyl-1-yl-quinoline or a pharmaceuticallyacceptable salt thereof, is administered more than once a day.